A number of medicines are guanidines. These guanidines include cyclized guanidines of the general formula 1.
__________________________________________________________________________ 1 #STR1## COMPOUND R R.sub.1 R.sub.2 n R.sub.3 __________________________________________________________________________ PRAZOSIN H Me Me 1 #STR2## - TERAZOSIN H Me Me 1 #STR3## - DOXAZOSIN H Me Me 1 #STR4## - TIODAZOSIN H Me Me 1 #STR5## - TRIMAZOSIN OMe Me Me 1 #STR6## - QUINAZOSIN H Me Me 1 #STR7## - BUNAZOSIN H Me Me 2 ##STR8## __________________________________________________________________________
Thus the include the following cyclized guanidines of general formula 2.
______________________________________ Cyclized Guanidines 1 #STR9## ______________________________________ R.sub.1 = R.sub.2 = Me; R.sub.3 = TERAZOSIN - R.sub.1 = R.sub.2 = Me; R.sub.3 = PRAZOSIN - R.sub.1 = R.sub.2 = Me; R.sub.3 = DOXAZOSIN ______________________________________
The following compounds are exemplary ##STR13## These guanidines also include uncyclized guanidine of the general formula 3.
__________________________________________________________________________ 3 #STR14## __________________________________________________________________________ BETHANIDINE; R'.sub.1 = R'.sub.3 = H; R'.sub.5 = R'.sub.4 = Me; R'.sub.2 = #STR15## - MEOBENTINE; R'.sub.1 = R'.sub.3 = H; R'.sub.5 = R'.sub.4 = Me; R'.sub.2 = ##STR16## __________________________________________________________________________
wherein Me is CH.sub.3 (methyl).
The prior art preparations of cyclized and uncylized guanidines for example of Terazosin (R.sub.3 =tetrahydrofuryl), Prazosin (R.sub.3 =furyl), Doxazosin (R.sub.3 =1,4,-benzodioxan-2-yl), and Meobentine (R'.sub.1 =4-methoxybenzyl, R'.sub.2 =H, R'.sub.3 =methyl, R'.sub.4 =H, R'.sub.5 =CH.sub.3) are discussed below.
Compounds of general formulae 1 have been prepared by a number of approaches which may be classified into five general methods.
In method 1, a 4-amino-6,7-dimethoxy quinazoline that is substituted at C-2 position with a good leaving group X, is condensed with a proper amine. Up to nine steps are used to synthesize the 4-amino-6,7-dimethoxy quinazoline, starting from veratraldehyde [J. Chem. Soc. 1759, (1948) and J. Med. Chem. 20, 146, (1977)].
______________________________________ METHOD 1 #STR17## - #STR18## - X Reference ______________________________________ Cl Fr. Pat. 2321890 Fr. Pat. 2350101 Can Pat. 1057754 Can Pat. 1081229 Ger Pat. 2707068 Ger Pat. 2725019 Eur Pat. 0034471 U.S. Pat. No. 4251532 U.S. Pat. No. 4026894 Brit Pat. 1156973 Brit Pat. 2021108 SCH.sub.3 Ger Pat. 2707068 Brit Pat. 1156973 Brit Pat. 2021108 SO.sub.2 alkyl Brit Pat. 2021108 ______________________________________
Those fine chemical manufacturers synthesizing prazosin terazosin, and doxazosin for the most part use this process or a modification thereof. The major shortcoming of this method (method 1) is the low yields (between about 5 and 25%) which may be ascribed to the large number of steps involved.
In method 2, a 3,4-dimethoxyaniline that is substituted at the C-6 position with a nitrile, amide or amidine group is condensed with an amine that is N-substituted with an appropriate functional group, Y.
______________________________________ METHOD 2 #STR19## - #STR20## - C-6(Z) Y Reference ______________________________________ CN CN Brit Pat. 1390014 Brit Pat. 1390015 Eur Pat. 0034471 CN H.sub.2 N--C.dbd.NH Brit Pat. 1156973 CN H.sub.2 N--C.dbd.NH Brit Pat. 1156973 (C1 instead of NH.sub.2 at C-1 position) CN H--N.dbd.C--O-Alkyl Ger Pat. 2457911 CN H--N.dbd.C--S-Alkyl Ger Pat. 2457911 O--C--NH.sub.2 CN Ger Pat. 2457911 HN.dbd.C--NH.sub.2 CN Ger Pat. 2457911 ______________________________________
The processes taught by German Patent 2457911 propose the use of highly toxic cyanogen bromide. The yields of the processes are poor at best and thus not attractive for commercial production.
In method 3,3,4-dimethoxy-6-cyanoaniline is converted to its corresponding isothiocyanate using thiophosgene. This is then condensed with a proper amine. The resulting thiourea is then S-alkylated (e.g. methyl iodide). High temperature reflux in the presence of ammonium chloride results in the insertion of the amine group. followed by ring closure to afford Terazosin (Bel. Pat. PCT/F18200034, Eur. Pat. 00340471). However thiophosgene is extremely toxic and its use is not practical on commercial scale due to high cost and limited availability. ##STR21##
In method 4, N-cyano-N-(3,4-dimethoxyphenyl)-5-methylisothiourea [see J. Heterocycl. Chem. 23, 401 (1986) or Hungarian Pat. 181743] is condensed with a proper amine to afford a carboxamidine which upon heating at high temperature affords the desired product (Can. Pat. 2015066, Eur. Pat. 0034471). The reported yields starting from the thioether is 63%. However, the thioether itself is difficult to manufacture. ##STR22##
In method 5, 2-chloro-4-amionquinazoline is initially condensed with piperazine and the resulting amine is reacted with an acid chloride to afford the desired product (Brit. Pat. 1156973). ##STR23##
As in method 1, this process also fails to provide good yields, because of the number of steps involved in the preparation of the 2-chloroquinazoline starting material.
These methods suffer from various other shortcomings. For example, the use of 2-chloro-4-amino-6,7-dimethoxyquinazoline (method 1 and 5) is prohibitive due to the fact its synthesis involves nine steps from veratraldehyde and the overall yield is approximately 5-25% [F.H.S. Curd et. al., J. Chem. Soc. 1759 (1948) and J. Med. Chem. 20, 146 (1977)].
Activation of the amine group (method 2) requires the use of highly toxic cyanogen bromide (Y.dbd.CN), followed by further modification of the activating group (Y.dbd.H.sub.2 N-C.dbd.NH, HN.dbd.C-O-Alkyl). Use of ammonium thiocyanate, followed by altylation of sulfur, will result in Y.dbd.HN.dbd.C-S-Alkyl. Nevertheless, the yields are generally low (ca. 40%). In method 3, although the reported yield of prazosin is high (ca. 68%), high toxicity and limited commercial availability of thiophosgene renders the method unattractive. In method 4, the overall yield starting from N-cyano N'-((3,4-dimethoxyphenyl)-S-methyl-isothiourea is reported to be ca. 63%. Nevertheless, the requirement of this isothiourea as starting material the preparation of which being very difficult and inefficient, renders the method unattractive.
Compounds of general formula 3 are synthesized using S-alkylated thiourea and the corresponding amine. The synthesis of Meobentine has been reported is U.S. Pat. No. 3,949,089 as described below. ##STR24##
The use of thiophosgene to manufacture thiourea is limited due to its high toxicity and commercial unavailability. Use of ammonium thiocyanate on the other hand followed by alkylation of the resulting thiourea generally affords low overall yields and therefore suffers from the same disadvantages described in the methods 2 and 3 (vide sudra).
It is therefore an object of this invention to provide improved more efficient methods for the synthesis of compounds such as ureas and guanidines for example cyclized guanidines such as 2-amino substituted quinazolines of general formula 1 (e.g. Terazosin, Prazosin, Doxazosin, Tiodazosin, Trimazosin. Quinasin and Bunazosin) and for example uncyclized guanidines such as those of general formula 3 (e.g. Meobentine and bethanidine).
It is a further object of the invention to provide such improved more efficient processes which produce the desired compounds for example guanidines and ureas and in higher yields than in the prior art.
It is still a further object of the invention to provide such compounds for example quinazolines of very high purity (therefore having the desired efficacy).
It is still further object of this invention to provide (manufacture) novel intermediates including ureas and guanidines suitable for use to synthesize other guanidines for example 2-amino-substituted quinazolines including Terazosin. Prazosin, and Doxazosin and other guanidines for example meobentine and Bethanidine.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of the embodiments thereof.